DESCRIPTION: Many perimenopausal women experience hot flashes during mid-life. Hot flashes often have serious consequences, including fatigue, irritability, and acute physical discomfort that affects work and quality of life. Despite the high prevalence and importance of hot flashes, little is known about their risk factors. The proposed project will test the hypotheses that smoking, genetic polymorphisms in cytochrome P450 (CYP450) enzymes, and low serum estrogen levels are associated with an increased risk of hot flashes. It also will assess the hypothesis that smoking and CYP45O polymorphisms are associated with hot flashes via mechanisms that lower estrogen levels. The specific aims are to: 1) determine whether cigarette smoking is associated with risk of hot flashes, 2) evaluate whether CYP45O polymorphisms are associated with risk of hot flashes, 3) assess whether low levels of serum estrogens are associated with risk of hot flashes, and 4) determine whether women exposed to both smoking and genetic polymorphisms have a different risk of hot flashes than women exposed to one or none of these risk factors. To complete the study, 400 perimenopausal women (45-54 years) with hot flashes (200 cases) or without hot flashes (200+ controls) will be recruited from Baltimore and the surrounding areas. Each participant will complete a questionnaire that assesses hot flash and smoking history, other potential risk factors, and potential confounders. Participants also will provide blood samples for analysis of estrogen levels and CYP450 genetic polymorphisms. Associations between hot flashes, smoking, estrogen levels, and CYP450 polymorphisms then will be assessed using appropriate statistical and analytic methods. The results of this study will provide information about risk factors for perimenopausal hot flashes, particularly the influence of smoking, CYP450 polymorphisms, and serum estrogen levels. These results ultimately may be useful for future studies on the prevention and/or treatment of hot flashes.